Depression in the medically ill is a significant public health concern, occurring in up to 50% of patients and having a significant impact on treatment adherence, quality of life, and morbidity and mortality. New developments in the conceptualization of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines have been found to influence neurobiologic function including neurochemistry and behavior, and induce a depressive syndrome that has overlapping features with major depression. The long term objective of the proposed work is to further understand the neural correlates of this cytokine-induced depression as it relates to depression in the medically ill. As a model system, we plan to study patients receiving the cytokine, interferon (IFN) alpha, for the treatment of hepatitis C. IFN alpha is a potent inducer of proinflammatory cytokines (especially interleukin 6) and leads to depressive symptoms in 30-50% of patients depending on the dose. Preliminary data from our lab indicate that IFN alpha treatment is associated with reduced evoked activity in the striatum and medial prefrontal cortex as determined by functional magnetic resonance imaging (fMRI). These findings, in conjunction with clinical evidence of impaired functioning of the basal ganglia (e.g. reduced reaction time, psychomotor slowing, akathesia and anhedonia) in IFN alpha-treated patients, suggest that dysfunction of fronto-striatal neurocircuitry may underlie IFN alpha-induced depressive symptoms and may represent a critical pathway by which cytokines induce depression. The fundamental hypothesis of the proposed work is that IFN alpha-induced depression begins with reduced activation of striatal neurons that is associated with psychomotor slowing and anhedonia and in turn contributes to reduced activity in the prefrontal cortex. Reduced activity in the prefrontal cortex is then associated with the development of depressive symptoms and cognitive dysfunction. Thus, we hypothesize that reduced evoked activity in the striatum will 1) be predictive of the development of depressive symptoms during IFN alpha therapy, 2) will precede the development of reduced activity in the prefrontal cortex, and 3) will be a predominent feature of IFN alpha-induced depression compared to depression in medically healthy individuals. To test these hypotheses, we plan to conduct fMRIs and neuropsychiatric assessments in 40 patients with hepatitis C at various time points during IFN alpha therapy. Results will be compared to control populations of hepatitis C patients awaiting IFN alpha treatment (N=20) and medically healthy subjects with and without major depression (N=20 per group). Results from these studies will provide important new data on neural pathways by which cytokines induce depression and will establish a foundation for developing novel strategies to diagnose and treat depression in the medically ill.